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Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

ABSTRACT: WD-repeat proteins are implicated in a variety of biological functions, most recently in oncogenesis. However, the underlying function of WD-repeat protein 41 (WDR41) in tumorigenesis remains elusive. The present study was aimed to explore the role of WDR41 in breast cancer. Combined with Western blotting and immunohistochemistry, the results showed that WDR41 was expressed at low levels in breast cancer, especially in triple-negative breast cancer (TNBC). Using methylation-specific PCR (MSP), we observed that WDR41 presented hypermethylation in MDA-MB-231 cells. Methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) management increased the expression of WDR41 in MDA-MB-231 cells, but not in MCF-10A (normal mammary epithelial cells) or oestrogen receptor-positive MCF-7 breast cancer cells. WDR41-down-regulation promoted, while WDR41-up-regulation inhibited the tumour characteristics of TNBC cells including cell viability, cell cycle and migration. Further, WDR41-up-regulation dramatically suppressed tumour growth in vivo. Mechanistically, WDR41 protein ablation activated, while WDR41-up-regulation repressed the AKT/GSK-3? pathway and the subsequent nuclear activation of ?-catenin in MDA-MB-231 cells, and 5-aza-dC treatment enhanced this effect. After treatment with the AKT inhibitor MK-2206, WDR41-down-regulation-mediated activation of the GSK-3?/?-catenin signalling was robustly abolished. Collectively, methylated WDR41 in MDA-MB-231 cells promotes tumorigenesis through positively regulating the AKT/GSK-3?/?-catenin pathway, thus providing an important foundation for treating TNBC.

SUBMITTER: Wang H

PROVIDER: S-EPMC7299681 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

Wang Han H Wu Dan D Cai Liangliang L Li Xiaohong X Zhang Zhiming Z Chen Shuai S

Journal of cellular and molecular medicine 20200512 12

WD-repeat proteins are implicated in a variety of biological functions, most recently in oncogenesis. However, the underlying function of WD-repeat protein 41 (WDR41) in tumorigenesis remains elusive. The present study was aimed to explore the role of WDR41 in breast cancer. Combined with Western blotting and immunohistochemistry, the results showed that WDR41 was expressed at low levels in breast cancer, especially in triple-negative breast cancer (TNBC). Using methylation-specific PCR (MSP), w ...[more]

PMID: 32394588

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Project description:BackgroundThe disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles have been attributed to desmosomal structures in different cancer entities. In the present study, we describe the pro-metastatic role of the desmosomal protein desmocollin 2 (DSC2) in breast cancer.MethodsWe analysed the prognostic role of DSC2 at mRNA and protein level using microarray data, western blot analysis and immunohistochemistry. Functional consequences of DSC2 overexpression and DSC2 knock down were investigated in the triple negative breast cancer (TNBC) cell line MDA-MB-231 and its brain-seeking subline MDA-MB-231-BR, respectively in vitro and in vivo.ResultsWe found a significantly higher DSC2 expression in the more aggressive molecular subtypes HER2-positive and TNBC than in luminal breast cancers, as well as a significant correlation between increased DSC2 expression and a shorter disease-free-also in multivariate analysis-and overall survival. Additionally, a significant association between DSC2 expression in the primary tumour and an increased frequency of cerebral and lung metastasis could be observed. In vitro, ectopic DSC2 expression or DSC2 down-regulation in MDA-MB-231 and MDA-MB-231-BR led to a significant tumour cell aggregation increase and decrease, respectively. Furthermore, tumour cells displaying higher DSC2 levels showed increased chemoresistance in 3D structures, but not 2D monolayer structures, suggesting the importance of cell aggregation as a means for reduced drug diffusion. In an in vivo brain dissemination xenograft mouse model, reduced expression of DSC2 in the brain-seeking TNBC cells led to a decreased amount of circulating tumour cells/clusters and, in turn, to fewer and smaller brain metastatic lesions.ConclusionWe conclude that high DSC2 expression in primary TNBC is associated with a poorer prognosis, firstly by increasing tumour cell aggregation, secondly by reducing the diffusion and effectiveness of chemotherapeutic agents, and, lastly, by promoting the circulation and survival of tumour cell clusters, each of which facilitates distant organ colonisation.

Project description:Aberrant methylation is one of the most frequent epigenetic alterations that regulate the expression levels of genes, including long non‑coding RNAs (lncRNAs), in tumors. However, to the best of our knowledge, the expression and function of hepatic nuclear factor 1α antisense RNA 1 (HNF1A‑AS1) and its methylation condition have not yet been reported in the development and progression of laryngeal squamous cell carcinoma (LSCC). In the present study, the expression and methylation of HNF1A‑AS1 were first examined by reverse transcription‑quantitative PCR, bisulfite genomic sequencing and methylation‑specific polymerase chain reaction in samples from patients with LSCC, which were based on the in silico analysis using The Cancer Genome Atlas data, and were then further verified in LSCC cell lines with and without 5‑Aza‑2'‑deoxycytidine (5‑Aza‑dC) treatment. Subsequently, proliferation, cell cycle distribution, migration and invasion of LSCC cells following either knockdown or overexpression of HNF1A‑AS1 were determined in vitro. Furthermore, the characteristic of HNF1A‑AS1 on epithelial‑mesenchymal transition (EMT) changes was investigated in vitro and in vivo. The associations between the expression levels of HNF1A‑AS1 and tumorigenicity and cervical lymph node metastasis were assessed in a xenograft model in nude mice. In the present study, downregulation and hypermethylation in CpG sites of HNF1A‑AS1 were detected in LSCC tissues as well as metastatic cervical lymph nodes samples when compared with those in the adjacent non‑tumor tissues. Additionally, HNF1A‑AS1 inhibited proliferation, migration and invasion of LSCC cells in vitro by regulating the process of EMT. Furthermore, HNF1A‑AS1 inhibited tumor growth and metastasis by regulating EMT in vivo. Additionally, the migration and invasion abilities, and the expression levels of HNF1A‑AS1 and EMT markers in LSCC cells were significantly reversed by treatment with 5‑Aza‑dC. In summary, HNF1A‑AS1 was downregulated by hypermethylation in LSCC and laryngeal cancer cells. These findings suggested that HNF1A‑AS1 could serve as a tumor suppressor lncRNA in LSCC by regulating the EMT process, leading to the discovery of novel therapeutic targets and strategies for the treatment of patients with LSCC.

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Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

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Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

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